In breakthrough research, researchers from Pennsylvania University have reported a pathway which can prevent tumors from developing. Researchers believe they have discovered the “Achilles Heel” of cancers based on experiments in both human cells and mouse models.

Discovered pathway uses the ATF4 protein, which when blocked causes cancer cells to over-produce protein and die. Latest findings could open the door to a completely new approach. Because inhibitors that can block ATF4 synthesis already exists.

According to researchers, ATF4 protein functions as the partner of the MYC gene. Myc is one of the most frequently mutated and overexpressed gene associated with cancer. This gene codes for the myc protein (a transcription factor) which controls a variety of cellular functions including cell growth and apoptosis. Myc protein triggers a sequence of reactions that helps tumor cells grow uncontrollably. Currently, there is no way to target the gene, but past studies have shown that blocking other targets in the chain can hamper tumor development.

ATF4 is at a point after both pathways come back together (Credit: Penn Medicine)

Prof Koumenis’s team from Perelman School of Medicine of the University of Pennsylvania found that some tumors are controlled by PERK kinase, responsible for ATF4 (Activating transcription factor 4) activation. In the latest study, they showed that blocking PERK may not always prevent the development of tumors. Because MYC effectively controls a second pathway that can operate in parallel making PERK redundant. This research found second kinase, GCN2.

“What we’ve learned is that we need to go further downstream to block tumor growth in a way that cancer cells can’t easily escape, and our study identifies the target to do just that,” said Koumenis, co-senior author of this study.

The study published in Nature Cell Biology suggests an alternative strategy is to target ATF4 itself, as it is the point where both signal pathways converge, resulting in less redundancy. The results also indicate that ATF4 turns on the genes MYC needs for growth and regulates the rate at which cells produce proteins called 4E-BP. When ATF4 was knocked out in human cells or mice, tumor cells continued to build up 4E-BP proteins and eventually died because of stress. This prevented lymphoma and colorectal cancer development in mice.

In MYC associated tumors, ATF4 and its protein partner 4E-BP are also over-expressed, which is further proof that these results may lead to a strategy that might work in humans.

“This shows us the potential impacts of targeting ATF4 in MYC-dependent tumors, something we’re already studying. We’re also working to confirm this approach will not cause any serious off-target effects,” said lead author Feven Tameire.

According to researchers, future studies will explore why ATF4 works the way it does, which may assist them in finding other potential therapies.